KR102424837B1 - Emulsion formulations of aprepitant - Google Patents

Abstract

Disclosed herein are novel pharmaceutical formulations of aprepitant suitable for parenteral administration, including intravenous administration. Also included are formulations comprising both aprepitant and dexamethasone sodium phosphate. The pharmaceutical formulations are stable oil-in-water emulsions for the parenteral treatment of emesis and are particularly useful for the treatment of subjects undergoing highly emetic cancer chemotherapy.

Description

Emulsion formulation of aprepitant {EMULSION FORMULATIONS OF APREPITANT}

related Cross-reference to application

This application claims the benefit of U.S. Provisional Application No. 62/052,948, filed on September 19, 2014, the specification of which is incorporated by reference in its entirety.

technical field

The present specification relates generally to emulsion formulations and systems for intravenous or parenteral administration of aprepitant for the treatment of emesis. Emulsion formulations are stable for long periods of time. Also described are methods for preparing stable aprepitant emulsions and pharmaceutical formulations.

Chemical name 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4- Aprepitant with morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one has the structure:

Aprepitant is indicated for the prevention of acute and delayed nausea and vomiting associated with early and repeat courses of highly emetic cancer chemotherapy. Although aprepitant is currently available as an oral capsule in the United States, it is desirable to formulate aprepitant as a liquid suitable for parenteral or intravenous administration due to the nausea and vomiting experienced by patients.

It is very difficult to prepare a liquid formulation containing aprepitant because aprepitant is a molecule with poor solubility and poor permeation properties. One means of addressing this challenge is to prepare emulsions that not only allow the preparation of injectable formulations, but can also enhance the bioavailability of aprepitant when administered.

Intravenous emulsions should have very small droplet sizes to circulate in the bloodstream without causing capillary occlusion and embolism. This size limitation is typified by USP33-NF28 General Chapter <729> (hereafter referred to as USP <729>) on Globule Size Distribution in Lipid Injectable Emulsions in Injectable Emulsions, which (1) 500 to a population of large diameter fat globules, expressed as a volume-weighted percentage of fat greater than 5 μm (PFAT5), with an average droplet size not exceeding nm or 0.5 μm and (2) not exceeding 0.05%, irrespective of the final lipid concentration. limit universal restrictions on

The emulsion formulation should be physically stable. The droplet size limits defined in USP <729> apply throughout the allotted shelf life. All true emulsions are thermodynamically unstable and may undergo various processes that tend to increase droplet size over time. These include direct droplet coalescence, when two droplets collide to form one new droplet, and agglomeration, in which the droplets attach together to form a larger mass. Agglomeration may in some cases be a precursor to further coalescence into larger droplets. In these processes large aggregates can form on the surface of the vessel, resulting in a phenomenon known as 'creaming' and ultimately leading to visible free oil on the emulsion surface known as 'cracking'. have.

The emulsion formulation must also be chemically stable. The drug substance may be degraded; For example, a lipophilic drug will split into an oil phase that confer some protection, but hydrolytic degradation may still occur at the oil-water interface. Possible chemical degradation in parenteral fat emulsions includes the oxidation of unsaturated fatty acid residues present in triglycerides and lecithin, and hydrolysis of phospholipids, leading to the formation of free fatty acids (FFAs) and lysophospholipids. These degradants lower the pH, which may then promote further degradation. Thus, pH must be controlled during manufacture and parenteral emulsion formulations may include buffers to provide additional control. Any decrease in pH during the allotted shelf life may indicate chemical degradation.

In the present application, an emulsion formulation has been prepared and it is characterized by identifying a formulation and process that allows aprepitant to be included in an emulsion for intravenous injection and remains stable during the shelf life of the formulation.

The following aspects described and exemplified below and embodiments thereof are typical and illustrative, but not intended to be limiting in scope.

In one embodiment, an oil phase comprising aprepitant, a surfactant and a cosurfactant; and a stable emulsion comprising an aqueous phase comprising water, a tonicity agent and a pH-adjusting agent. In some embodiments, the pH-adjusting agent is a buffer.

In one embodiment, the composition comprises structurally modified or hydrolyzed coconut oil, olive oil, soybean oil, safflower seed oil, triglycerides, octyl and decyl glycerates, ethyl oleate, glyceryl linoleate, ethyl linoleate, an oil-in-water emulsion comprising an oil selected from the group consisting of glyceryl oleate, cholesteryl oleate/linoleate or mixtures thereof.

In one embodiment, the composition comprises from about 5% (wt/wt%) to 15%, 5% to 10%, 7% to 10%, or 8% to 9% oil by weight. In another embodiment, the oil is soybean oil. (In this specification, weight % means weight / weight %.)

In one embodiment, the composition comprises about 10% to 20% by weight, 12% to 17% by weight, 13% to 16% by weight, 13% to 15% by weight, or 13% to 14% by weight of an emulsifier. include In another embodiment, the composition comprises about 13 wt%, 13.5 wt%, 14 wt%, 14.5 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, or 20 wt% emulsifier include In another embodiment the emulsifier is lecithin. In another embodiment the lecithin is egg yolk lecithin.

In one embodiment, the composition comprises about 20% to 50%, 30% to 50%, 35% to 45%, 30% to 45%, 37% to 42%, 38% by weight. % to 40% by weight, 30% by weight, 31% by weight, 32% by weight, 33% by weight, 34% by weight, 35% by weight, 36% by weight, 37% by weight, 38% by weight, 39% by weight, 40% by weight; 41% by weight, 42% by weight, 43% by weight, 44% by weight, 45% by weight, 46% by weight, 47% by weight, 48% by weight, 49% by weight, 50% by weight of oil; and as a percentage of the weight of the oil per sum of the weights of oleate. In another embodiment, the oil is soybean oil.

In one embodiment, the composition comprises about 40% to 80%, 50% to 70%, 55% to 65%, 57% to 63%, 58 to 60%, 35% to 35% by weight. 40 wt%, 30 wt% to 40 wt%, 50 wt%, 51 wt%, 52 wt%, 53 wt%, 54 wt%, 55 wt%, 56 wt%, 57 wt%, 58 wt%, 59 wt% %, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70% by weight of an emulsifier; It is expressed as a percentage of the weight of the emulsifier per sum of the weights of oil, emulsifier and oleate in the unit composition. In another embodiment the emulsifier is lecithin. In another embodiment the lecithin is egg yolk lecithin.

In one embodiment, the ratio of oil to aprepitant (wt%:wt%) in the composition is about 11:1 to 20:1, 11:1 to 15:1, 12:1 to 16:1, 12:1 to 14:1, 11:1 to 15:1, 12:1 to 14:1, 12.5:1 to 13.5:1, 13:1 to 14:1, or 12:1 to 15:1. In another embodiment, the ratio of oil to aprepitant (wt%:wt%) in the composition ranges from about 11:1 to 20:1, 11:1 to 15:1, 12:1 to 16:1, 12:1 to 14:1, 11:1, 11.5:1, 12:1, 12.5:1, 13:1, 13.5:1, 14:1, 14.5:1 or 15:1, 15.5:1, 16: 1 is

In one embodiment, the ratio of emulsifier to aprepitant (wt%:wt%) in the composition is from about 15:1 to 30:1, 20:1 to 25:1, 18:1 to 22:1 or 10:1 to 30:1. In another embodiment, the ratio of emulsifier to aprepitant (wt%:wt%) in the composition is about 15:1, 18:1, 19:1, 20:1, 21:1, 22:1 23:1 , 24:1, or 25:1.

In one embodiment, the ratio of (emulsifier plus oil) to aprepitant (wt%:wt%) in the composition is about 20:1 to 40:1, 25:1 to 35:1, 30:1 to 35:1 to be. In another embodiment, the ratio of oil: aprepitant is about 25:1, 26:1, 27:1, 28:1, 29:1 30:1, 31:1, 32:1, 33:1, 34:1, 35:1, 36:1, 37:1, 38:1 or 40:1 ranges.

In one embodiment, the ratio of emulsifier to oil (wt%:wt%) in the composition is about 0.5:1, to 4:1, 1:1 to 2:1, or 1.25:1 to 1.75:1. In another embodiment, the ratio of emulsifier to oil (wt%:wt%) in the composition is about 0.5:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2:1, 1.05:1, 1.15:1, 1.25: 1, 1.35:1, 1.45:1, 1.55:1, 1.65:1, 1.75:1, 1.85:1, or 1.95:1 range.

In one embodiment, the therapeutic dose is about 1-4 g, 1.5-3 g, 1.8-2.8 g, 2.3-2.8 g, 1.8-2.3 g, 1 g, 1.1 g, 1.2 g, 1.3 g, 1.4 g, 1.5 g, 1.6 g, 1.7 g, 1.8 g. 1.9 g, 2 g, 2.1 g, 2.2 g, 2.3 g, 2.4 g, 2.5 g, 2.6 g, 2.7 g, 2.8 g. 2.9 g, 3 g, 3.1 g, 3.2 g, 3.3 g, 3.4 g, 3.5 g, 3.6 g, 3.7 g, 3.8 g. 3.9 g, 4 g emulsifier. In another embodiment, the emulsifier is lecithin. In another embodiment the emulsifier is egg yolk lecithin.

In one embodiment, the therapeutic dose is about 0.5 to 3 g, 1 to 2.5 g, 1 to 2 g, 1 to 1.5 g, 1.5 g to 2 g, 0.5 g, 0.6 g, 0.7 g, 0.8 g, 0.9 g, 1 g, 1.1 g, 1.2 g, 1.3 g, 1.4 g, 1.5 g, 1.6 g, 1.7 g, 1.8 g. 1.9 g, 2 g, 2.1 g, 2.2 g, 2.3 g, 2.4 g, 2.5 g oil. In another embodiment, the oil is soybean oil.

In one embodiment, the emulsifier is a phospholipid. In another embodiment, the emulsifier is egg phospholipid, soy phospholipid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, phosphatidic acid, mixed chain phospholipid, lysophospholipid, hydrogenated phospholipid, partially hydrogenated phospholipids, and mixtures thereof.

In one embodiment, the composition comprises a cosurfactant. In another embodiment, the cosurfactant is ethanol.

In one embodiment, the composition comprises from about 0% to 10% by weight, from 1% to 9% by weight, or from 2% to 6% by weight of a cosurfactant. In another embodiment, the composition comprises less than 10%, less than 9%, less than 8%, less than 7, less than 6%, less than 5%, less than 4%, less than 3%, less than 2% by weight. or less than 1% by weight of a cosurfactant.

In one embodiment, the composition comprises about 0% to 10%, 1% to 9%, or 2% to 6% ethanol by weight. In another embodiment, the composition comprises less than 10%, less than 9%, less than 8%, less than 7, less than 6%, less than 5%, less than 4%, less than 3%, less than 2% by weight. or less than 1% by weight of ethanol.

In one embodiment, the emulsion comprises an aqueous phase comprising an entericity adjusting agent, a pH-adjusting agent, and water.

In one embodiment, the emulsion comprises an aqueous phase comprising an osmotic agent, a pH-adjusting agent, and water.

In one embodiment, the emulsion comprises an aqueous phase comprising an entericity adjusting agent, an osmolality agent, a pH-adjusting agent, and water.

In one embodiment, the aqueous phase further comprises a buffer.

In one embodiment, the aqueous phase comprises a buffer but no pH-adjusting agent other than the buffer. In another embodiment, the buffer functions as both a pH-adjusting agent and a buffer.

In another embodiment, when the aqueous phase comprises a buffer, the composition does not contain an entericity control agent.

In yet another embodiment, the buffer is selected from the group consisting of phosphate buffer, citrate buffer, Tris buffer, carbonate buffer, succinate buffer, maleate buffer and borate buffer. In another embodiment, the buffer is selected from the group of phosphate buffered saline (PBS), modified PBS (PBS-mod) and citrate buffer.

In one embodiment, the aqueous phase comprises a buffer that, when mixed with the oil phase, provides an oil-in-water emulsion that is substantially isotonic.

In one embodiment, the osmolality agent is selected from the group consisting of glycerol, sorbitol, xylitol, mannitol, glucose, trehalose, maltose, sucrose, raffinose, lactose, dextran, polyethylene glycol, or propylene glycol. In another embodiment, the osmolality agent is an inorganic salt such as sodium chloride and mixtures thereof.

In one embodiment, the pH adjusting agent is from the group consisting of sodium hydroxide, potassium hydroxide, magnesium hydroxide, sodium carbonate, Tris, sodium linoleate, sodium oleate, potassium carbonate, potassium linoleate, potassium oleate, and mixtures thereof. is selected from

In one embodiment, the composition has a pH of about 6 to 9, 7 to 9, 7.5 to 9, 7.5 to 8.5, 8 to 9, 6 to 8, 7 to 8, or 6, 7, 8 or 9.

In one embodiment, the composition comprises about 0% to 25% by weight, 2% to 20% by weight, 3% to 15% by weight, or 3% to 8% by weight of the consistency agent. In another embodiment, the composition comprises about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% by weight, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, or 20 wt%, 21 wt%, 22 wt%, 23 wt% weight %, 24 weight %, 25 weight % strength control agent. In another embodiment, the composition does not include a bowel control agent.

In one embodiment, the composition comprises about 0% to 25% by weight, 2% to 20% by weight, 3% to 15% by weight, or 3% to 8% by weight of the osmotic agent. In another embodiment, the composition comprises about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% by weight, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, or 20 wt%, 21 wt%, 22 wt%, 23 wt% % by weight, 24% by weight, 25% by weight of the osmotic agent. In yet another embodiment, the composition does not include an osmotic agent.

In one embodiment, the aqueous phase comprises a dose of dexamethasone sodium phosphate in a dose of the composition. In another embodiment, the dose of dexamethasone sodium phosphate ranges from about 0.5 mg to 30 mg, 0.5 mg to 25 mg, 1 mg to 20 mg, 10 mg to 20 mg, or 3 mg to 16 mg. In another embodiment, the dose of dexamethasone sodium phosphate is about 9 mg or 16 mg of the composition dose.

In one embodiment, the oily phase comprises a dose of dexamethasone in a dose of the composition. In another embodiment, the dexamethasone dose ranges from about 0.5 mg to 30 mg, 0.5 mg to 20 mg, 1 mg to 18 mg, 10 mg to 20 mg, or 3 mg to 16 mg. In another embodiment, the dexamethasone dose is about 8 mg or 12 mg of the composition dose.

In one embodiment, the emulsion comprises about 0.002% to 0.2%, 0.003% to 0.16%, 0.02% to 0.1% dexamethasone sodium phosphate by weight.

In one embodiment, the composition has a dynamic light scattering (DLS) of about 50 nm to 1000 nm, 50 to 500 nm, 50 nm to 400 nm, 50 nm to 300 nm, 50 nm to 200 nm or 50 nm to 100 nm. It is a stable system that maintains the strength-weighted average particle size determined by In another embodiment, the average droplet size is maintained above 500 nm at room temperature for a period of at least 1 month, 3 months, 6 months, 9 months, 12 months, 2 years or 3 years. In another embodiment, the average droplet size is maintained above 500 nm at 5°C for a period of at least 1 month, 3 months, 6 months, 9 months, 12 months, 2 years or 3 years.

In another aspect, a method for preparing an emulsion comprising aprepitant and suitable for parenteral administration is provided.

In one embodiment, the administration is intravenous administration.

In one embodiment, the method comprises the steps of a) preparing an oil phase by dissolving aprepitant and an emulsifier in ethanol and then adding to the oil to produce an oil-based mixture; b) preparing an aqueous phase by mixing water, optionally with an enteric acidity agent, optionally an osmolality agent and optionally a pH modifying agent and optionally a buffer, to form an aqueous mixture; c) combining the oil-based mixture and the aqueous mixture and homogenizing it at high speed to produce a crude emulsion; and d) high pressure homogenizing the crude emulsion to produce a fine emulsion.

In one embodiment, preparing the oil phase further comprises dissolving dexamethasone in ethanol together with aprepitant and an emulsifier.

In one embodiment, the method comprises the steps of: a) preparing an oil phase by dissolving aprepitant and an emulsifier in ethanol and oil to produce an oil-based mixture; b) preparing an aqueous phase by mixing water, optionally with an enteric acidity agent, optionally an osmolality agent and optionally a pH modifying agent and optionally a buffer, to form an aqueous mixture; c) combining the oil-based mixture and the aqueous mixture and homogenizing it at high speed to produce a crude emulsion; and d) high pressure homogenizing the crude emulsion to produce a fine emulsion.

In one embodiment, preparing the oil phase further comprises dissolving dexamethasone in ethanol and oil together with aprepitant and an emulsifier.

In one embodiment, preparing the aqueous phase further comprises mixing the dexamethasone with water, a lengthening agent, a pH modifying agent, and a buffer. In another embodiment, the dexamethasone is a salt of dexamethasone. In another embodiment, the dexamethasone is dexamethasone sodium phosphate.

In one embodiment, the method further comprises sterilizing the fine emulsion to produce a final emulsion, wherein the final emulsion is suitable for injection into a subject.

In one embodiment, dissolution in ethanol is at a temperature of about 25°C to 80°C, 40°C to 75°C, 60°C to 70°C, or about 25°C, 35°C, 45°C, 60°C, 65°C, 70 ℃ or 75 ℃.

In one embodiment, the high speed homogenization is performed at a speed of about 2,000 rpm (revolutions per minute) to 25,000 rpm. In another embodiment, the high speed homogenization is performed at a speed of about 20,000 rpm. In yet another embodiment, the high speed homogenization is performed at a speed of about 3600 rpm.

In one embodiment, the high speed homogenization is performed for a period of about 0.5 minutes to 1 hour, 1 minute to 45 minutes, or 1 minute to 30 minutes. In another embodiment, the high speed homogenization is performed for a period of about 20 to 40 minutes or for about 30 minutes.

In one embodiment, the high-speed homogenization is performed at about 10°C to about 60°C, 20°C to about 60°C, about 30°C to about 50°C, or about 35°C to about 45°C. In another embodiment, the high-speed homogenization is performed at about 25°C, 30°C, 35°C, 40°C, 45°C or 50°C.

In one embodiment, the high pressure homogenization is performed at a pressure of about 10,000 psi (pounds per square inch) to 30,000 psi. In another embodiment, the high pressure homogenization is performed at a pressure of about 20,000 psi.

In one embodiment, the high pressure homogenization is performed with cooling. In another embodiment, the high pressure homogenization may reduce the temperature of the emulsion at the outlet of the process within a period of time from about 0 °C to about 60 °C, from about 10 °C to about 40 °C, from about 20 °C to about 30 °C, or from about 20 °C, This is done with sufficient cooling to bring to 25°C or 30°C.

In one embodiment, sterilizing the fine emulsion comprises filtering the fine emulsion through a nylon filter. In another embodiment, the nylon filter is a Posidyne® filter. In yet another embodiment, the filter has a pore size of about 0.2 μm (micrometers).

Additional embodiments, such as compositions and methods, will become apparent from the following description, drawings, examples, and claims. As can be appreciated from the foregoing and the description that follows, each and every feature described herein, and each and every combination of two or more of these features, is the included within the scope. In addition, any feature or combination of features may be specifically excluded from any embodiment of the invention. Additional aspects and advantages of the present invention are set forth in the following description and claims, particularly when considered in conjunction with the accompanying examples and drawings.

1 provides microscopic images of the samples of Examples 1, 2, 3 and 6 after a freeze-thaw cycle. A: Example 1, B: Example 2, C: Example 3, D: Example 6
Figure 2 shows plasma levels of aprepitant after injection of phosaprepitant solution (-) or an aprepitant emulsion (▲) prepared as described herein.
Figure 3 shows the plasma levels of aprepitant after injection of a solution of phosaprepitant (▲) or after injection of an emulsion (●) containing aprepitant and dexamethasone prepared as described herein.
4 shows plasma levels of dexamethasone after injection of a solution of dexamethasone sodium phosphate (?) or after injection of an emulsion containing aprepitant and dexamethasone prepared as described herein (▲).

Various aspects will now be described more fully hereinafter. However, these aspects may be embodied in many different forms and should not be construed as limited to the embodiments presented herein; Rather, these embodiments are provided so that this specification will be thorough and complete, and will fully convey its scope to those skilled in the art.

I. Definition

As used herein, singular expressions include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "polymer" includes a single polymer, as well as two or more of the same or different polymers, and reference to "excipient" includes a single excipient, as well as two or more of the same or different excipients. do.

Where a range of values is provided, the value falling between the upper and lower limits of that range and any other stated value or intervening value within the stated range is encompassed by this specification. For example, if a range of 1 μm to 8 μm is recited, 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, and 7 μm, as well as ranges of values equal to or greater than 1 μm and 8 μm The ranges of values below are also intended to be expressly disclosed. As used herein, the term “about” means ±5%, ±10%, or ±20% of the said value being varied.

The term "emulsion" or "emulsion formulation" refers to a colloidal dispersion of two immiscible liquids in the form of droplets, typically 10 nanometers to 100 microns in diameter. Emulsions are denoted by the symbol O/W (oil-in-water) when the continuous phase is an aqueous solution and W/O (water-in-oil) when the continuous phase is oil. Other examples of emulsions, such as O/W/O (oil-in-water), include oil droplets contained within droplets of an aqueous phase dispersed in a continuous oil phase.

"Physically stable" emulsions will meet the criteria under USP <729>, which define universal restrictions for (1) an average droplet size not exceeding 500 nm or 0.5 μm and (2) a population of large diameter fat globules. It is expressed as the volume-weighted percentage of fat greater than 5 μm (PFAT5) not to exceed 0.05% at 5°C or at room temperature during the specified storage period. In addition, physically stable emulsions will have no visible aprepitant crystals upon storage at 5° C. or room temperature for a specified period of time. Crystals are considered visible when viewed at magnifications of 4X to 10X. Emulsions are physically stable if they meet the criteria under USP <729> and are stored at 5° C. or room temperature for a period of not more than 1 week, 2 weeks, 4 weeks, 1 month, 2 months, 6 months, 1 year, or 2 years. Can't see aprepitant crystals.

"Chemically stable" emulsions herein are those in which the concentration of the active ingredient (ie, the drug to be delivered) does not change by more than about 20% for at least one month under appropriate storage conditions. In certain embodiments, the concentration of aprepitant in the emulsions herein is about 5%, 10% for at least 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, or 24 months under suitable storage conditions. , does not change more than 15% or 20%.

In one embodiment, the stable emulsion compositions herein are stable over a wide range of temperatures, for example, -20°C to 40°C. The compositions herein may be stored at about 5°C to about 25°C.

"Oil phase" in a water-in-oil emulsion refers to all components of the formulation that individually exceed the solubility limit of the aqueous phase; These are generally substances with a solubility of less than 1% in distilled water, but aqueous phase components such as salts may reduce the solubility of certain oils, resulting in partitioning into the oil phase. Oil phase refers to the non-aqueous phase portion of a water-in-oil emulsion.

"Aqueous phase" or "water phase" in a water-in-oil emulsion refers to the water present and any component that is water soluble, ie, does not exceed the solubility limit of water. "Aqueous phase", as used herein, includes pharmaceutically acceptable additives such as acidifying agents, alkalizing agents, buffering agents, chelating agents, complexing and solubilizing agents, antioxidant and antimicrobial preservatives, humectants, suspending agents. water-containing liquids, which may contain topical and/or viscosity modifiers, entericity modifiers and wetting agents or other biocompatible materials. The aqueous phase refers to the non-oily portion of the water-in-oil emulsion.

"Emulsifier" refers to a compound that inhibits the separation of an injectable emulsion into an oily and aqueous phase, respectively. Emulsifiers useful herein are generally (1) compatible with the other ingredients of the stable emulsion herein, (2) do not interfere with the stability or efficacy of the drug contained in the emulsion, and (3) stable in the formulation. and does not deteriorate, and (4) is non-toxic.

Suitable emulsifiers include propylene glycol mono- and di-fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, polyoxyethylene-polyoxypropylene copolymers and block copolymers, salts of fatty alcohol sulfates, sorbitan fatty acids esters, esters of polyethylene-glycol glycerol ethers, oil and wax based emulsifiers, glycerol monostearate, glycerin sorbitan fatty acid esters and phospholipids.

"Phospholipid" refers to a triester of glycerol with two fatty acids and one phosphate ion. Exemplary phospholipids useful in the present invention are phosphatidyl chloride, lecithin (a mixture of choline esters of phosphorylated diacylglycerides), phosphatidylethanolamine, phosphatidylglycerol, from about 4 to about 22 carbon atoms, and more typically from about 10 to about phosphatidic acids having 18 carbon atoms and varying degrees of saturation. Phospholipids can have any combination of fatty acids as fatty acyl side chains, for example, phospholipids are saturated fatty acids such as decanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid, icosic acid, (C20 saturated fatty acids); sodium behenic acid, or unsaturated fatty acids such as myristoleic acid, palmitoleic acid, oleic acid, sodium linoleic acid, alpha linolenic acid, sodium arachidonic acid, eicosapentanoic acid, and the like. The two fatty acyl residues on phospholipids may be the same or may be different fatty acids. The phospholipid component of the drug delivery composition may be a single phospholipid or a mixture of several phospholipids. Phospholipids should be acceptable for the route of administration selected.

In one embodiment, the phospholipids used as emulsifiers in the present invention are naturally occurring phospholipids from natural origin. For example, naturally occurring lecithin is a mixture of diglycerides of stearic acid, palmitic acid, and oleic acid, bound to a choline ester of phosphoric acid, commonly called phosphatidylcholine, and can be obtained from a variety of sources, such as eggs and soybeans. have. Soy lecithin and egg lecithin (including hydrogenated versions of these compounds) have been characterized in various compositions and are generally recognized as safe, have combined emulsifying and solubilizing properties, and more rapidly than most synthetic surfactants. It tends to decompose into harmless substances.

The term "lecithin" includes complex mixtures of acetone-insoluble phosphatides, of which phosphatidylcholine is an important component. The term lecithin is also used as a synonym for phosphatidylcholine. Useful lecithins include, but are not limited to, egg yolk-, egg-, soy-, and corn-derived lecithins. In one embodiment, the emulsifier is lecithin, eg, egg yolk-derived lecithin. The terms egg lecithin and egg yolk derived lecithin are used interchangeably throughout. The compositions described herein preferably include lecithin as an emulsifier.

The amount of phospholipids in the emulsion of the present specification, based on weight, is about 10% to about 20% by weight, 11% to 19% by weight, 11% to 15% by weight, 12% to 13% by weight, 13% by weight. % to 14 wt%, 13 wt% to 20 wt%, or 12 wt% to 18 wt%. In certain embodiments, the phospholipids in the emulsion are, by weight, at a concentration of about 11%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, or 15% by weight. exist.

"Oil" refers to an organic liquid of mineral, vegetable, animal, essential or synthetic origin, including, for example, aliphatic or wax-based hydrocarbons, aromatic hydrocarbons or mixed aliphatic and aromatic hydrocarbons.

The term "buffer" or "buffered" as used herein refers to a solution containing a weak acid and its conjugate base, the pH of which changes only slightly upon addition of an acid or base. As used herein, the phrase “buffering agent” refers to a species included in a solution to provide a buffered solution.

The term “therapeutic agent” describes any natural or synthetic compound having biological activity.

II. aprepitant emulsion and manufacturing method

The present specification relates to a stable pharmaceutical composition comprising an aprepitant, a surfactant or a mixture of surfactants, a cosurfactant, an oil with an aqueous phase. The composition is in the form of an oil-in-water emulsion that remains stable for an extended period of time and is suitable for dilution and intravenous administration.

Active agents such as aprepitant are present in the oil phase together with emulsifiers, coemulsifiers and oils. The oily phase is then combined with an aqueous phase comprising water and a tonicity control agent as described below to produce a stable emulsion. Prior to combining the oil phase with the aqueous phase, the oil phase will have an oil:aprepitant ratio of about 13:1. The use of this ratio surprisingly results in an oil:aprepitant ratio of less than about 12:1 or 11:1, and/or greater than about 15:1, 20:1, or 30:1 of the oily phase when mixed with the aqueous phase. was found to produce more stable emulsions compared to emulsions containing

Moreover, the composition also has good stability properties when the amount of emulsifier in the oil phase is greater than the amount of oil. For example, the oil phase contains an emulsifier:oil ratio of about 5:1 to 1:1, 3:1 to 1:1 or a ratio of about 1.5:1. This emulsifier:oil ratio was surprisingly found to impart greater stability to the final emulsion suitable for injection into a patient. For example, an aprepitant emulsion having a phospholipid:oil ratio in the oil phase of about 1.5:1 was found to have greater stability than a similar aprepitant emulsion, the oil phase being about 0.01:1, 0.1:1, 0.5: a phospholipid:oil ratio of 1 or 0.9:1.

1. Paid

The oily phase (hydrophobic phase) comprises oil. Triglycerides are exemplary oils used in the compositions described herein. In certain embodiments the oil is or comprises a vegetable oil. "Vegetable oil" refers to an oil derived from plant seeds or nuts. Vegetable oils are typically formed when three fatty acids (usually 14 to 22 carbons in length, with varying numbers and positions of unsaturated bonds depending on the source of the oil) form ester bonds with three hydroxyl groups on glycerol. long-chain triglycerides" (LCT). In certain embodiments, highly refined grades (also called "ultra-refined") vegetable oils are used to ensure the safety and stability of oil-in-water emulsions. In certain embodiments hydrogenated vegetable oils produced by controlled hydrogenation of vegetable oils may be used. Exemplary vegetable oils are almond oil, babassu oil, black currant seed oil, borage oil, canola oil, castor oil, coconut oil, corn oil, cottonseed oil, olive oil , peanut oil, palm oil, palm kernel oil, rapeseed oil, safflower seed oil, soybean oil, sunflower oil and sesame oil. Hydrogenated and/or partially hydrogenated forms of these oils may be used. In a specific embodiment, the oil is or comprises safflower seed oil, sesame oil, corn oil, olive oil and/or soybean oil. In a more specific embodiment, the oil is or comprises safflower seed oil, and/or soybean oil. The oil is present at about 9% by weight in the emulsion, although it may vary between about 5% and 12% by weight or between 9% and 10% by weight.

Aprepitant is first mixed with an emulsifier, for example a phospholipid emulsifier. Examples 1, 2, 3 and 6 below describe emulsions prepared using egg lecithin. The phospholipid emulsifier is added at a concentration greater than 10%, 11%, 12% or 13% by weight of the emulsion, but less than 15%, 17% or 20% by weight of the emulsion.

The mixture of aprepitant and emulsifier is dissolved in a coemulsifier, for example a short chain alcohol (1 to 6 carbons). In Examples 1, 2, 3 and 6 below, the co-emulsifier is ethanol. The mixture is mixed at an elevated temperature, eg, an elevated temperature such as about 60°C or 70°C, or an elevated temperature in the range of about 50°C or 70°C, until the aprepitant and the emulsifier are dissolved. This mixture is then combined with an oil, eg, soybean oil, by mixing again at an elevated temperature, eg, about 60°C, to produce an oily phase containing aprepitant. Excess coemulsifier can be removed by standard evaporation methods, including heating, or reduced pressure, or combinations thereof, used in rotary evaporators. In this process, about 10% to 100%, 20% to 95%, 80% to 100%, 90% to 100%, or 95% to 100% of the ethanol evaporates at the production scale, optional reduced pressure, and heating time. follow

In one embodiment, the aprepitant and the emulsifier are dissolved in the co-emulsifier and the oil. In Examples 1, 2, 3 and 6 below, the co-emulsifier is ethanol and the oil is soybean oil, however, the method may be used with any one or more of the co-emulsifiers and oils described herein. The mixture is prepared at an elevated temperature, for example, at an elevated temperature such as about 60°C or 70°C, or at an elevated temperature in the range of about 50°C or 70°C, until the aprepitant and the emulsifier are dissolved to form a mixture containing the aprepitant. prepare the oil phase. The mixture of aprepitant, emulsifier, coemulsifier and oil is mixed at elevated temperature for about 15 minutes to 120 minutes, about 15 minutes to 45 minutes, about 30 minutes to 90 minutes, or about 15 minutes, 30 minutes or 50 minutes. .

Excess co-emulsifier can be removed by standard evaporation methods including heating in a rotary evaporator, or reduced pressure, or a combination thereof. During this process, about 10% to 100%, 20% to 95%, 80% to 100%, 90% to 100%, or 95% to 100% of the ethanol evaporates at the production scale, optional reduced pressure, and heating time. follow

In one embodiment, dexamethasone is added to an oil phase comprising aprepitant, an emulsifier and an oil prior to mixing with the aqueous phase to form a pharmaceutical emulsion for injection to produce an oily phase comprising aprepitant and dexamethasone. Dexamethasone is added to the oil phase to provide a dose of about 12 mg dexamethasone.

2. aqueous phase

The aqueous phase of the aprepitant emulsion may be a mixture of water and a bowel control agent including, but not limited to, such as sucrose, mannitol, glycerin or dextrose or mixtures thereof. A pH-adjusting agent is also included in the aqueous phase. Sodium oleate is used in Examples 1, 2 and 3 below to adjust the pH of the emulsion to about 6 to 9 depending on the desired emulsion formulation. The aqueous phase is produced by mixing water with sodium oleate as an enteric and pH adjusting agent. Other pH modifiers that may be used include, but are not limited to, sodium hydroxide, potassium hydroxide, magnesium hydroxide, Tris, sodium carbonate, and sodium linoleate. The pH modifier used is effective to adjust the pH of the emulsion to a preferred pH of about 6 to 9, 7 to 8, or about 6, 7, 8 or 9. The aqueous phase can be readily formed by mixing at room temperature.

The aqueous phase may further contain a buffer to promote stability of the emulsion formulation. The drug substance may be degraded; For example, a lipophilic drug will partition into an oil phase, which confer some protection, but still hydrolytic degradation may occur at the oil-water interface. Possible chemical degradations within parenteral fat emulsions include oxidation of unsaturated fatty acid residues present in triglycerides and lecithin, and hydrolysis of phospholipids leading to the formation of free fatty acids (FFAs) and lysophospholipids. These decomposition products lower the pH, which may then promote decomposition. Thus, the pH must be controlled during manufacture and the emulsion formulation may contain buffers to provide additional control. A decrease in pH during the allotted shelf life may be indicative of chemical degradation. Suitable buffers are well known to those skilled in the art and include, but are not limited to, phosphate buffer, citrate buffer, Tris buffer, carbonate buffer, succinate buffer, maleate buffer or borate buffer. Tris buffer is used to adjust the pH of the emulsion to about 8 to 9 in Example 11 below. In certain embodiments, the buffer is selected from the group of phosphate buffered saline (PBS), modified PBS (PBS-mod) and citrate buffer. In certain embodiments, the aqueous phase comprises a buffer that, when mixed with the oil phase, provides an oil-in-water emulsion that is substantially isotonic.

Buffers useful in the described compositions of the present invention include, but are not limited to, phosphate buffer, citrate buffer, Tris buffer, carbonate buffer, succinate buffer, maleate buffer or borate buffer. In certain embodiments, the buffer is selected from the group of phosphate buffered saline (PBS), modified PBS (PBS-mod) and citrate buffer. In certain embodiments, the aqueous phase comprises a buffer that, when mixed with the oil phase, provides a substantially isotonic oil-in-water emulsion. In some embodiments, when the aqueous phase contains a buffer, the aqueous phase does not include a tonicity control agent. Also, when the buffer is added to the aqueous phase, the pH-adjusting agent may not be added to the aqueous phase. It is understood that the buffer may be added to the aqueous phase or the buffer may be added to the emulsion.

In some embodiments, the aqueous phase contains a tonicity control agent such as sucrose. The consistency agent is added (wt/wt) to the aqueous phase having about 0% to 30%, 0% to 25%, or about 20% of the consistency agent. It was surprisingly found that compositions containing about 20% by weight sucrose in the aqueous phase produce particularly stable emulsions as determined by freeze-thaw tests. Accordingly, preferred embodiments provide for an aqueous phase difference as compared to an emulsion wherein the aqueous phase contains less than about 10%, 15%, or 20% by weight of a tonicity control agent or greater than about 30%, 40% or 50% by weight of the tonicity control agent. emulsions comprising a bowel control agent that impart greater chemical and/or physical stability.

In one embodiment, the aqueous phase further comprises sodium dexamethasone phosphate (also called “dexamethasone phosphate”). Dexamethasone sodium phosphate is a corticosteroid that is freely soluble in water. The daily dosage for dexamethasone sodium phosphate ranges from about 0.5 mg to 20 mg, more preferably from about 14 mg to 18 mg or 16 mg, depending on the severity of the disease or disorder. Accordingly, the aprepitant emulsion further comprising dexamethasone may contain sodium dexamethasone phosphate in the aqueous phase. Accordingly, the aqueous phase of the emulsion suitable for intravenous administration may contain about 0.5 mg to 20 mg, 14 mg to 18 mg, or about 16 mg dexamethasone sodium phosphate.

In another embodiment, a solution of sodium dexamethasone phosphate can be mixed into a fine emulsion prior to sterile filtration to prepare an emulsion containing sodium dexamethasone phosphate in an aqueous phase.

3. Aprepitant Emulsion

The pharmaceutical aprepitant composition of the present specification is a sterile oil-in-water emulsion comprising an aqueous phase and an oil phase as described above. Also included herein are methods for the preparation of stable emulsions comprising aprepitant, which are suitable for intravenous administration and which may be prepared according to conventional manufacturing procedures using aseptic techniques.

The aqueous phase is combined with the oil phase under high speed homogenization to produce a coarse emulsion. As described in Examples 1, 2, 3, 4, 5 and 6, the combined aqueous and oil phases are homogenized using an IKA Ultra-Turrax T25 dispersing instrument at a speed of 20,000 rpm for 1 minute. The speed used in this first homogenization step may vary, for example, from 2000 rpm to 25,000 rpm, or from 15,000 rpm to 22,000 rpm. The time of the homogenization step may also vary, for example, from 0.5 minutes to 1 hour, or from 1 minute to 45 minutes. This crude emulsion is then homogenized into a fine emulsion by means of a high-pressure homogenizer, which may be a microfluidizer. The interaction chamber and cooling coil portions of the microfluidizer are cooled by water, for example by an ice bath. The temperature of the ice bath may be 0 to 10°C, or 2 to 6°C. The temperature of the emulsion exiting the high pressure homogenization may be from 0 to 60°C, from 15°C to 60°C, from 20°C to 40°C, or about 25°C. The microfluidizer first provides water and then the crude emulsion is introduced. The output from the homogenizer is initially wasted in removing the priming water and emulsion mixture, then collected in a clean vessel when the stream becomes apparently constant. The high pressure homogenizer cycle may be repeated to sufficiently reduce the droplet size. The pressure used for homogenization may vary. The pressure may be between 5000 and 30,000 psi. The number of passes through the microfluidizer may be varied to achieve the desired droplet size. The number of passes may be about 2 to 20, 2 to 15, 4 to 15, 4 to 12, or 7 to 8 passes.

The pharmaceutical formulation may then be passed through a filter system at room temperature and/or autoclaved to achieve sterilization. The filter used to achieve sterilization may be selected by one of ordinary skill in the art and may have a nominal pore size of 0.2 μm. The filter material used may vary. In one embodiment, the filter is nylon. In another embodiment, the filter is a Posidyne® filter (a shared charge-modified Nylon 6,6 membrane exhibiting a net positive-charge zeta potential in aqueous solution). For large scale production the method may need to be modified. One of ordinary skill in the art may combine these materials in other orders and using different processing equipment to achieve the desired end goal result.

In one embodiment herein, the homogenization may be performed in repeated cycles with intermediate cooling of the homogenized product to a temperature of less than about 25° C. to achieve an emulsion having an oil particle/spheroid size of less than 2 microns (μm).

The final emulsion comprises an oily portion (oil phase) dispersed in an aqueous portion (aqueous phase). The ratio of the components in the oil phase to aprepitant is an important characteristic of an emulsion that may affect the stability of a formulation prepared for injection. As described above, the oily phase includes aprepitant, an oil and an emulsifier, examples of which are provided herein.

The final aprepitant emulsion contains 0.7 wt% aprepitant, but may range from about 0.2 wt% to 1.5 wt%, 0.4 wt% to 1.0 wt% or 0.6 wt% to 0.7 wt%. Although emulsions containing about 130 mg aprepitant are prepared, formulations containing about 100 mg to 1000 mg, 100 mg to 500 mg, 250 mg to 750 mg or 100 mg to 200 mg aprepitant are also described herein. It can also be manufactured according to

In one embodiment, the ratio of oil: aprepitant (wt%:wt%) in the oil phase is about 11:1 to 15:1, 12:1 to 14:1, 13:1 to 13.5:1, 13:1 to 14:1, or 12:1 to 15:1. In another embodiment, the ratio of oil: aprepitant is about 11:1, 11.5:1, 12:1, 12.5:1, 13:1, 13.5:1, 14:1, 14.5:1 or 15:1 to be.

The ratio of emulsifier to aprepitant may also vary. For example, the ratio of emulsifier to aprepitant (wt%:wt%) in the oil fraction is about 15:1 to 30:1, 20:1 to 25:1, 18:1 to 22:1 or 10:1. to 30:1. In one embodiment, the emulsifier:aprepitant (wt%:wt%) is about 15:1, 18:1, 19:1, 20:1, 21:1, 22:1 or 23:1.

The ratio of the components in the oil phase may alternatively be expressed as the ratio (emulsifier plus oil):aprepitant (wt%:wt%). Ratios contemplated herein may range from about 20:1 to 40:1, 25:1 to 35:1, 30:1 to 35:1 or 33:1 to 37:1, or, for example, about 30:1, 32:1, 33:1, 34:1, 35:1, 36:1, 37:1, 38:1 or 40:1.

The compositions herein have significant advantages in terms of reduced toxicity compared to injectable formulations which may contain less desirable excipients such as detergents, for example, Tween-20 or Tween-80. This formulation exploits the ability to solubilize a therapeutically effective amount of aprepitant in an oily phase that can then be used to create an emulsion suitable for injection. Accordingly, disclosed herein is a pharmaceutical emulsion composition containing aprepitant and optionally dexamethasone or dexamethasone sodium phosphate, said emulsion comprising no detergent.

The compositions herein provide products suitable for parenteral use due to their small particle size. The compositions herein are easy to use because the product can be diluted with an agent such as an aqueous solution of sucrose, an aqueous solution of maltose or dextrose 5% injection or physiological saline to achieve the concentrations required for parenteral administration. The compositions herein also have an extended shelf life and are therefore suitable for readily marketable products.

The compositions herein are both chemically and physically stable. The physically stable emulsions of the present invention can be maintained for at least 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 24 or 36 months without an acceptable average droplet size increase as noted in USP <729>. It can be stored under suitable conditions for a long time. Also, the population of large-diameter fat districts must be within the limits stated in USP <729>.

The droplet size limits defined in USP <729> apply throughout the allotted shelf life, which may be extended to 2-3 years or more for commercial pharmaceutical formulations. All true emulsions are thermodynamically unstable and may undergo various processes that tend to increase droplet size over time. These include direct droplet coalescence, when two droplets collide to form one new droplet, and agglomeration, where the droplets attach together to form a larger mass. Agglomeration may in some cases be a precursor to further coalescence into larger droplets. In these processes large aggregates can form on the surface of the vessel, resulting in a phenomenon known as 'creaming' and ultimately leading to visible free oil on the emulsion surface known as 'cracking'. have.

Droplet size measurements, such as those defined in USP<729>, can measure an initial increase in size and are therefore predictive of emulsion physical stability initially, long before the formulation exhibits visible changes. Accordingly, the emulsions described herein are stable compositions having an intensity-weighted average droplet diameter of less than about 500 nm, 400 nm, 300 nm, 200 nm, or 100 nm.

The oil or particle droplet size, ie diameter, according to the invention is measured using a dynamic light scattering (DLS) instrument, for example a Malvern Zetasizer 4000, a Malvern Zetasize Nano S90 or preferably a Malvern Zetasizer Nano ZS. Intensity-weighted particle sizes were recorded as they do not require knowledge of the refractive index of the particles. In the Malvern Zetasizer instrument, there are two fits for determining the intensity-weighted diameter of droplet size. The first is the cumulative fit used to determine the Z-mean diameter; This fit may additionally provide a polydispersity index (PDI). This cumulative rate fit is recommended for monovariate samples with a PDI of less than 0.2. The second is a non-negative least squares (NNLS) fit. It provides Peak 1 diameter, Peak 2 diameter and Peak 3 diameter. This is more suitable for polydisperse samples with a PDI greater than 0.2.

Emulsion formulations as described herein may further comprise a preservative in an amount that preserves the composition. Suitable preservatives used in some embodiments herein include disodium ethetate, tocopherol, benzalkonium chloride, methyl, ethyl, propyl or butylparaben, benzyl alcohol, phenylethyl alcohol, benzalkonium, chlorobutanol, potassium sorbate or combinations thereof, but are not limited thereto.

III. medical use

The pharmaceutical compositions herein can be used for the prevention or treatment of vomiting and provide a non-oral option to patients undergoing severe or moderate emetic chemotherapy. Accordingly, the present specification includes a method of treatment comprising intravenously administering an aprepitant emulsion as described herein to a subject undergoing severe or moderate emetic chemotherapy.

Another embodiment relates to the use of a pharmaceutical formulation herein in the manufacture of a medicament for use in the prevention or treatment of vomiting in a subject in need thereof.

The amount of aprepitant and optionally dexamethasone required for use in the methods herein may vary depending on the method of administration and the condition of the patient, and the extent of treatment required, and is ultimately at the discretion of the attending physician or clinician.

IV. Example

The following examples are illustrative in nature and in no way limiting.

For intravenous injection aprepitant emulsion Produce

Example One

To prepare the aprepitant emulsion, an oily phase was first prepared by combining 750 mg of aprepitant and 15.0 g of egg lecithin (LIPOID E 80) with 12.0 ml of ethanol. The mixture was dissolved by heating and stirring at 60° C. and 200 rpm for 15 minutes. To the resulting solution was added 10.0 g of soybean oil. Heating at 60° C. and stirring at 200 rpm were continued for another 15 minutes. The aqueous phase was prepared by dissolving 5.60 g of sucrose and 0.500 g of sodium oleate in 70.0 ml of water for injection. The mixture was stirred at 300 rpm at room temperature for 30 minutes. A crude emulsion was prepared by adding the aqueous phase to the oil phase followed by high-speed homogenization (Ultra-Turrax® IKA T25) at a speed of 20,000 rpm for 1 minute. This crude emulsion was then passed eight times through an ice-cooled high pressure microfluidizer (Microfluidizer® M-110L, F12Y interaction chamber) at a pressure of 18,000 psi. The resulting fine emulsion was sterilized by passing it through a 0.2 μm nylon syringe filter (Corning). Details of the emulsion composition are provided in Table 1 below. Intensity-weighted particle size analyzed using a non-negative least squares (NNLS) fit by dynamic light scattering (Malvern® Zetasizer Nano ZS) gave a Peak 1 diameter of 99 nm. The intensity-weighted average particle size determined using the cumulative rate fit gave a Z-average diameter of 87 nm. The zeta potential was determined to be -43 mV by laser Doppler microelectrophoresis (Malvern® Zetasizer Nano ZS). The pH of the injectable emulsion was 8.74. This aprepitant-containing emulsion can be injected as is, or it can be diluted for injection with 5% dextrose or 0.9% saline.

ingredient Amount (g) Concentration (wt/wt%) Ratio to aprepitant aprepitant 0.750 0.679 One Lipoid E 80 15.0 13.6 20 soybean oil 10.0 9.05 13.3 ethanol ¹ 8.59 7.78 11.5 sucrose 5.60 5.07 7.5 sodium oleate 0.500 0.453 0.667 water for injection 70.0 63.4 93.3 Sum 110 100 -

¹ Final amount after taking into account evaporated ethanol during treatment.

Example 2

To prepare the aprepitant emulsion, an oily phase was first prepared by combining 450 mg of aprepitant and 9.00 g of egg lecithin (LIPOID E 80) with 4.0 ml of ethanol. The mixture was dissolved by heating and stirring at 60° C. and 200 rpm for 15 minutes. To the resulting solution was added 6.00 g of soybean oil. Heating at 60° C. and stirring at 200 rpm were continued for another 15 minutes. The aqueous phase was prepared by dissolving 3.36 g of sucrose and 0.300 g of sodium oleate in 42.0 ml of water for injection. The mixture was stirred at 300 rpm at room temperature for 30 minutes. A crude emulsion was prepared by adding the aqueous phase to the oil phase followed by high-speed homogenization (Ultra-Turrax® IKA T25) at a speed of 20,000 rpm for 1 minute. This crude emulsion was then passed eight times through an ice-cooled high pressure microfluidizer (Microfluidizer® M-110L, F12Y interaction chamber) at a pressure of 18,000 psi. The resulting fine emulsion was sterilized by passing it through a 0.2 μm nylon syringe filter (Corning). Details of the emulsion composition are provided in Table 2 below. Intensity-weighted particle size analyzed using NNLS fit by dynamic light scattering (Malvern® Zetasizer Nano ZS) gave a Peak 1 diameter of 127 nm. The intensity-weighted average particle size determined using the cumulative rate fit gave a Z-average diameter of 101 nm. The zeta potential was determined to be -47 mV by laser Doppler microelectrophoresis (Malvern® Zetasizer Nano ZS). The pH of the injectable emulsion was 8.77. This aprepitant-containing emulsion can be injected as is, or it can be diluted for injection with 5% dextrose or 0.9% saline.

ingredient Amount (g) Concentration (wt/wt%) Ratio to aprepitant aprepitant 0.450 0.714 One Lipoid E 80 9.00 14.3 20 soybean oil 6.00 9.52 13.3 ethanol ¹ 1.89 3.00 4.20 sucrose 3.36 5.33 7.47 sodium oleate 0.300 0.476 0.667 water for injection 42.0 66.7 93.3 Sum 63.0 100 -

¹ Final amount after taking into account evaporated ethanol during treatment.

Example 3

To prepare the aprepitant emulsion, an oily phase was first prepared by combining 450 mg of aprepitant and 9.00 g of egg lecithin (LIPOID E 80) with 6.0 ml of ethanol. The mixture was dissolved by heating and stirring at 60° C. and 200 rpm for 15 minutes. To the resulting solution was added 6.00 g of soybean oil. Heating at 60° C. and stirring at 200 rpm were continued for another 15 minutes. The aqueous phase was prepared by dissolving 15.62 g of sucrose and 0.300 g of sodium oleate in 42.0 ml of water for injection. The mixture was stirred at 300 rpm at room temperature for 30 minutes. A crude emulsion was prepared by adding the aqueous phase to the oil phase followed by high-speed homogenization (Ultra-Turrax® IKA T25) at a speed of 20,000 rpm for 1 minute. This crude emulsion was then passed eight times through an ice-cooled high pressure microfluidizer (Microfluidizer® M-110L, F12Y interaction chamber) at a pressure of 18,000 psi. The resulting fine emulsion was sterilized by passing it through a 0.2 μm nylon syringe filter (Corning). Details of the emulsion composition are provided in Table 3 below. Intensity-weighted particle size analyzed using NNLS fit by dynamic light scattering (Malvern® Zetasizer Nano ZS) gave a Peak 1 diameter of 88 nm. The intensity-weighted average particle size determined using the cumulative rate fit gave a Z-average diameter of 68 nm. The zeta potential was determined to be -42 mV by laser Doppler microelectrophoresis (Malvern® Zetasizer Nano ZS). The pH of the injectable emulsion was 8.80. This aprepitant-containing emulsion is to be diluted 4-fold with water for injection prior to injection.

ingredient Amount (g) Concentration (wt/wt%) Ratio to aprepitant aprepitant 0.450 0.587 One Lipoid E 80 9.00 11.7 20 soybean oil 6.00 7.83 13.3 ethanol ¹ 3.27 4.26 7.26 sucrose 15.6 20.4 34.7 sodium oleate 0.300 0.391 0.667 water for injection 42.0 54.8 93.3 Sum 76.6 100 -

¹ Final amount after taking into account evaporated ethanol during treatment.

Alternative for intravenous injection aprepitant emulsion formulation

Example 4

Aprepitant emulsions were prepared having less than 10% wt (% wt/wt) of phospholipid emulsifier and adjusted to a pH of less than 8.0. To prepare the aprepitant emulsion, an oily phase was first prepared by combining 450 mg of aprepitant and 6.67 g of egg lecithin (LIPOID E 80) with 7.2 ml of ethanol. The mixture was dissolved by heating and stirring at 60° C. and 200 rpm. Heating and dissolution were carried out until the ethanol evaporated and a thick residue was observed. 6.00 g of soybean oil and an appropriate amount of ethanol were added to the resulting solution, and a clear oily phase was obtained upon heating at 60°C. The aqueous phase was prepared by dissolving 3.36 g of sucrose in 50.5 ml of water for injection at 60°C. A crude emulsion was prepared by adding the aqueous phase to the oil phase followed by high-speed homogenization (Ultra-Turrax® IKA T25) at a speed of 20,000 rpm for 1 minute. The pH of this crude emulsion was adjusted to 7.0 and then passed 8 times through an ice-cooled high pressure microfluidizer (Microfluidizer® M-110L, F12Y interaction chamber) at a pressure of 18,000 psi. The resulting fine emulsion was sterilized by passing it through a 0.2 μm nylon syringe filter (Corning). Details of the emulsion composition are provided in Table 4 below. Crystals were observed in the product by microscopy within 4 days of preparation at room temperature.

ingredient Amount (g) Concentration (wt/wt%) Ratio to aprepitant aprepitant 0.450 0.672 One Lipoid E 80 6.67 9.95 14.8 soybean oil 6.00 8.96 13.3 sucrose 3.36 5.02 7.47 water for injection 50.5 75.4 112 Sum 67.0 100 -

Example 5

An aprepitant emulsion containing oleic acid was prepared. To prepare the aprepitant emulsion, an oily phase was first prepared by combining 250 mg of aprepitant, 2.50 g of egg lecithin (LIPOID E 80), 15.0 g of soybean oil and 125 mg of oleic acid. 10 ml of ethanol was added to dissolve the mixture at 70°C. Ethanol was removed by reduced pressure in a 70°C water bath to obtain a clear oily phase. A crude emulsion was prepared by adding the preheated aqueous phase containing 82.1 ml of water for injection at 70° C. to the oil phase followed by high-speed homogenization (Ultra-Turrax® IKA T25) at a speed of 20,000 rpm for 1 minute. This crude emulsion was passed 8 times through an ice-cooled high pressure microfluidizer (Microfluidizer® M-110L, F12Y interaction chamber) at a pressure of 18,000 psi. The resulting fine emulsion was sterilized by passing it through a 0.2 μm nylon syringe filter (Corning). Details of the emulsion composition are provided in Table 5 below. Crystals were observed in the product by microscopy within 4 days of preparation at room temperature.

ingredient Amount (g) Concentration (wt/wt%) Ratio to aprepitant aprepitant 0.250 0.250 One Lipoid E 80 2.50 2.50 10 soybean oil 15.0 15.0 60 oleic acid 0.125 0.125 0.5 water for injection 82.1 82.1 328 Sum 100 100 -

for intravenous injection aprepitant and dexamethasone sodium phosphate Preparation of emulsion containing

Example 6

To prepare an injectable emulsion containing aprepitant and dexamethasone sodium phosphate, an oily phase was first prepared by combining 773 mg of aprepitant, 15.5 g of egg lecithin (LIPOID E 80) with 10.3 ml of ethanol. The mixture was dissolved by heating and stirring at 60° C. and 200 rpm for 15 minutes. To the resulting solution was added 10.3 g of soybean oil. Heating at 60° C. and stirring at 200 rpm were continued for another 15 minutes. The aqueous phase was prepared by dissolving 5.77 g of sucrose and 0.515 g of sodium oleate in 71.1 ml of water for injection. The mixture was stirred at 300 rpm at room temperature for 30 minutes. A crude emulsion was prepared by adding the aqueous phase to the oil phase followed by high-speed homogenization (Ultra-Turrax® IKA T25) at a speed of 20,000 rpm for 1 minute. This crude emulsion was then passed eight times through an ice-cooled high pressure microfluidizer (Microfluidizer® M-110L, F12Y interaction chamber) at a pressure of 18,000 psi. Dexamethasone sodium phosphate (93.5 mg) dissolved in 1 ml of water for injection was mixed into a fine emulsion. The resulting fine emulsion containing both aprepitant and dexamethasone sodium phosphate was sterilized by passing it through a 0.2 μm nylon syringe filter (Corning). Details of the emulsion composition are provided in Table 6 below. Intensity-weighted particle size analyzed using NNLS fit by dynamic light scattering (Malvern® Zetasizer Nano ZS) gave a Peak 1 diameter of 95 nm. The intensity-weighted average particle size determined using the cumulative rate fit gave a Z-average diameter of 70 nm. The zeta potential was determined to be -43 mV by laser Doppler microelectrophoresis (Malvern® Zetasizer Nano ZS). The pH of the injectable emulsion was 8.92. This aprepitant and dexamethasone sodium phosphate containing emulsion can be injected as is, or diluted for injection with 5% dextrose or 0.9% saline.

ingredient Amount (g) Concentration (wt/wt%) Ratio to aprepitant aprepitant 0.773 0.688 One Dexamethasone Sodium Phosphate 0.0935 0.0832 0.121 Lipoid E 80 15.5 13.8 20 soybean oil 10.3 9.17 13.3 ethanol ¹ 7.31 6.51 9.47 sucrose 5.77 5.14 7.47 sodium oleate 0.515 0.459 0.667 water for injection 72.1 64.2 93.3 Sum 112 100 -

¹ Final amount after taking into account evaporated ethanol during treatment.

Example 7

room temperature and at 5℃ aprepitant emulsion stability

The stability of the aprepitant emulsions prepared as described in Examples 1, 2, 3 and 6 was measured by incubating each emulsion formulation at room temperature (about 25° C.) or at 5° C. The average particle size and percentage of fat globules greater than 5 μm were measured using DLS and light darkening, respectively, to determine if they met USP <729>. The emulsion was also examined microscopically for aprepitant crystals. Example 1 was stable for 2 months at room temperature. That is, the average particle size and percentage of fat globules greater than 5 μm satisfies USP <729>. Additionally, aprepitant crystals were not visible by microscopy. After 2 months of storage at room temperature, creaming was observed in Examples 1 and 6. This corresponds to the observation of aprepitant crystals. Examples 2 and 3 were stable at room temperature for 3 months and 2 months, respectively. After these time points, aprepitant crystals were observed in these formulations. Storage at 5° C. resulted in longer emulsion stability for Examples 1, 2, 3 and 6. Table 7 shows the characterization of Examples 1, 2, 3 and 6 and their respective stability at room temperature and 5°C.

Sample PDI Particle size as peak 1 diameter (nm) Particle size (nm) as Z-average diameter Zeta potential (mV) pH Stability at 25°C for USP<729>
(month) Stability at 5°C for USP<729> Example 1 0.122 99 87 -43 8.74 2 >10 months Example 2 0.200 127 101 -47 8.77 3 >10 months Example 3 0.219 88 68 -42 8.80 2 >10 months Example 6 0.244 95 70 -43 8.92 2 >10 months

Example 8

for freeze-thaw cycles aprepitant emulsion stability

Aprepitant emulsions prepared according to Examples 1, 2, 3 and 6 were tested for stability upon exposure to freeze-thaw cycles. Samples from Examples 1, 2, 3 and 6 were stored overnight at -20°C. They were thawed to room temperature the next day and visualized by microscopy. Prior to freezing, all samples were free of any visible particles under the microscope. 1 shows microscopic images at 10 times the emulsion after freeze-thaw cycles (Examples 1, 2, 3 and 6 are shown as FIGS. 1A, 1B, 1C, and 1D, respectively). Emulsions prepared as described in Examples 1, 2 and 6 showed visible particles after exposure to freezing. Only Example 3 was stable after freezing. No visible particles were observed for the formulation of Example 3 as FIG. 1C shows. This improved stability was brought about by the presence of a higher concentration of sucrose (20 wt/wt% in Example 3, compared to 5 wt/wt% in Examples 1, 2 and 6).

Example 9

The pharmacokinetics of the aprepitant emulsion prepared according to Example 1 were determined. Two groups of 6 male Sprague-Dawley rats were each injected intravenously with phosaprepitant in solution or an aprepitant emulsion prepared according to Example 1. All drugs were administered at effective concentrations corresponding to 14 mg/kg aprepitant. Blood from all rats was collected at appropriate time intervals and processed by centrifugation to obtain plasma. Plasma samples were analyzed by LC-MS/MS for aprepitant and phosafrepitant as appropriate. Plasma concentration versus time curves for aprepitant and for phosaprepitant for the emulsions described in Example 1 are provided in FIG. . The curve indicates that the initial aprepitant level reached immediately after injection of the aprepitant emulsion was almost three times higher than the initial aprepitant level reached immediately after injection of the phosaprepitant solution. However, the plasma levels of aprepitant resulting from each injection essentially equal essentially the same at the 3-hour time point, indicating that the formulations are bioequivalent except for a delay in the conversion of phosaprepitant to aprepitant.

Example 10

The pharmacokinetics of aprepitant and dexamethasone sodium phosphate combination emulsion prepared according to Example 6 were determined. Male Sprague-Dawley rats were treated with phosaprepitant solution (group 1), dexamethasone sodium phosphate solution (group 2), or an emulsion containing aprepitant and dexamethasone sodium phosphate prepared according to Example 6 (group 3), respectively. Injected intravenously. Groups 1 and 2 consisted of 6 rats each, and for group 3, 12 rats were injected with aprepitant and dexamethasone sodium phosphate combination emulsion to allow collection of sufficient samples for determination of both active ingredients. did

In groups 1 and 3, the dose was administered at an effective drug concentration corresponding to 2 mg/kg aprepitant. In groups 2 and 3, doses were administered at an effective drug concentration corresponding to 0.24 mg/kg dexamethasone sodium phosphate. Blood from all rats was collected at appropriate time intervals and processed by centrifugation to obtain plasma. Plasma samples were analyzed by LC-MS/MS for dexamethasone, aprepitant and phosaprepitant as appropriate.

3 and 4 provide plasma concentration versus time curves of aprepitant and dexamethasone, respectively. FIG. 3 compares aprepitant plasma concentration versus time curves resulting from injection of the emulsion described in Example 6 ( FIG. 3 , ?) versus injection of a solution of phosaprepitant ( FIG. 3 , ?). FIG. 4 compares dexamethasone plasma concentration versus time curves resulting from injection of dexamethasone sodium phosphate solution ( FIG. 4 , ● ) versus injection of the emulsion described in Example 6. FIG. The curve indicates that aprepitant in the emulsion is released approximately simultaneously with dexamethasone sodium phosphate. The presence of dexamethasone sodium phosphate in the emulsion does not affect the pharmacokinetics of aprepitant.

Example 11

To prepare the aprepitant emulsion with buffer, the oil phase is first prepared by combining 750 mg of aprepitant, 15.0 g of egg lecithin (LIPOID E 80), 10.0 g of soybean oil and 3.75 ml of ethanol. This mixture is dissolved by heating and stirring at 70° C. and 200 rpm for 30 minutes. The aqueous phase is prepared by dissolving 2.17 g of sucrose and 0.500 g of sodium oleate in a mixture of 4.1 ml of 1M Tris buffer (pH 8.4) and 65.9 ml of water for injection. The mixture is stirred at 300 rpm at room temperature for 30 minutes. A crude emulsion is prepared by adding the aqueous phase to the oil phase followed by high-speed homogenization (Ultra-Turrax® IKA T25) at a speed of 20,000 rpm for 1 minute. This crude emulsion is then passed eight times through an ice-cooled high pressure microfluidizer (Microfluidizer® M-110L, F12Y interaction chamber) at a pressure of 18,000 psi. The resulting fine emulsion is sterilized by passing it through a 0.2 μm nylon syringe filter (Corning). Dynamic light scattering is used to give Peak 1 diameter to determine intensity-weighted particle size using NNLS fit, and intensity-weighted average particle size is determined using cumulative rate fit to give Z-mean diameter do. Zeta potential is measured by laser Doppler microelectrophoresis (Malvern® Zetasizer Nano ZS). This aprepitant containing emulsion can be injected as is, or it can be diluted for injection with 5% dextrose or 0.9% saline.

While many exemplary aspects and embodiments have been discussed above, those skilled in the art will recognize variations, substitutions, additions, and subcombinations thereof. Therefore, the following appended claims and the claims hereafter introduced are to be construed to cover all such modifications, substitutions, additions and subcombinations as fall within the true spirit and scope of the claims herein.

Claims (17)

aprepitant;
11 wt/wt% to 15 wt/wt% egg lecithin;
5 wt/wt% to 15 wt/wt% oil;
a co-emulsifier which is 1 wt/wt% to 10 wt/wt% alcohol;
2 wt/wt% to 20 wt/wt% of a consistency modifier;
pH modifiers; and
An injectable emulsion comprising water, comprising:
wherein the pH of the emulsion ranges from 7.5 to 9.0. The emulsion according to claim 1, characterized in that the ratio of oil to aprepitant in the oil phase of the emulsion ranges from 10:1 to 15:1 (wt/wt%). The emulsion according to claim 1, characterized in that the ratio of emulsifier to aprepitant in the oil phase of the emulsion ranges from 15:1 to 30:1 (wt/wt%). The emulsion according to claim 1, characterized in that the ratio of emulsifier to oil ranges from 1:1 to 3:1 (wt/wt%). The emulsion of claim 1 further comprising sodium dexamethasone phosphate, wherein the sodium dexamethasone phosphate is in the aqueous phase. The emulsion according to claim 1, characterized in that the aprepitant is present in an amount of from 0.4 wt/wt% to 1.0 wt/wt%. The emulsion according to claim 1, characterized in that the egg lecithin is present in an amount of from 13 wt/wt% to 15 wt/wt%. The emulsion according to claim 1, wherein the pH modifying agent is sodium oleate. The emulsion according to claim 1, characterized in that the oil is soybean oil. The emulsion according to claim 1, wherein the alcohol is ethanol. The emulsion according to claim 1, characterized in that the ethanol is present in an amount of from 2 wt/wt% to 6 wt/wt%. 12. The emulsion according to any one of claims 1 to 11, further comprising a buffer. 13. The emulsion according to claim 12, wherein the buffer is a Tris buffer. combining an aprepitant, an emulsifier, and an alcohol with an oil to produce an oily phase;
combining water, a bowel control agent, a pH modifying agent, and optionally a buffer to produce an aqueous phase;
homogenizing the oil phase with the aqueous phase to produce a coarse emulsion premix;
homogenizing the coarse emulsion premix at a pressure of 10,000 to 30,000 psi using a microfluidizer to produce a pharmaceutical emulsion; and
A method for preparing a pharmaceutical emulsion comprising the step of sterilizing the pharmaceutical emulsion. 15. The method of claim 14, wherein the coarse emulsion premix comprises 4 to 15 passes through the microfluidizer. 15. The method of claim 14, wherein sterilizing comprises passing the pharmaceutical emulsion through a filter having a pore size of 0.2 microns. 17. The method according to any one of claims 14 to 16, further comprising adding a solution of dexamethasone sodium phosphate to the fine emulsion prior to sterile filtration.

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